JP2001078793A - Production of new pathologically active substance by fermentation method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a physiologically active substance useful as a chemotherapy medicine for malignant tumor, etc., by culturing a bacterium capable of producing physiologically active substance NK30, 424AS-1, etc., in an nutrient medium, forming and accumulating a product in the culture and collecting the culture. SOLUTION: A bacterium [e.g. Streptomyces sp. NA 30,101 strain (FERM P-16,422), etc.], belonging to the genus Streptomyces, capable of producing physiologically active substance NK30, 424AS-1, NK30, 424BS-1 or NK30, 424BS-2 of the formula is cultured in a nutrient medium to form and accumulate the compound of the formula in the culture. The compound is collected to give the objective physiologically active substance showing an inhibitory action on cell growth, useful as a chemotherapy medicine for malignant tumor, etc., exhibiting an inhibitory action on TNF α production and is useful as a therapeutic and prophylactic agent for chronic rheumatoid arthritis, Kawasaki disease, Crohn disease, Behcet's disease, bronchial asthma, canser cachexia, septicemia, hepatitis, cardiac failure, multiple sclerosis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel physiologically active substances NK30424AS-1, NK30424AS-2, N
K30424BS-1 and NK30424BS-2
A method for producing the same. The compound of the present invention exhibits a cell growth inhibitory effect and is expected as an anticancer substance used as a chemotherapeutic agent for malignant tumors. In addition, the compound of the present invention exhibits a TNFα production inhibitory effect, and is used for rheumatoid arthritis,
Kawasaki disease, Crohn's disease, Behcet's disease, bronchial asthma, cancer cachexia, sepsis, nephritis, hepatitis, vasculitis, heart failure, hyperlipidemia, multiple sclerosis, neuropathy, myelopathy, dementia, diabetes, virus It can be expected as a therapeutic or preventive for infectious diseases.

[0002]

2. Description of the Related Art Conventionally, as antitumor agents, adriamycin, mitomycin C and the like have been known. However, these have serious side effects and are not satisfactory in treatment, and the invention of compounds suitable for treatment of cancer has been awaited.

On the other hand, TNFα is produced not only from macrophages and monocytes, but also from many cells, and is known to exhibit various biological activities. Therefore, various diseases such as rheumatoid arthritis [Ann. Rheum. Dis. , Volume 49,
669 (1990)], Kawasaki disease [Clin. Immu
nol. Immunopathol. , 56, 29
P. (1990)], Crohn's disease [Arch. Dis. C
hill, 66, 561 (1991)], Behcet's disease [J. Rheumatol. , Volume 17, 11
07 (1990)], bronchial asthma [J. Allerg
y Clin. Immunol. 89, 958 (1992)], cancer cachexia [Immunol. Let
t. 11, 173 (1985)], sepsis [S
Science, Vol. 229, p. 869 (1986)], etc., show abnormal production of TNFα, and are considered to function as exacerbating factors for diseases. Furthermore, the involvement of TNFα has been suggested in diseases such as nephritis, hepatitis, vasculitis, heart failure, hyperlipidemia, multiple sclerosis, neuropathy, myelopathy, dementia, diabetes, and viral infection. Therefore, substances that suppress the production of TNFα are expected as therapeutic or prophylactic agents for these diseases, and the invention of useful TNFα production inhibitors has been awaited.

[0004]

An object of the present invention is to provide a method for producing a useful antitumor agent.

It is another object of the present invention to provide a method for producing a physiologically active substance having TNFα production inhibitory activity.

It is another object of the present invention to provide rheumatoid arthritis, Kawasaki disease, Crohn's disease, Behcet's disease, bronchial asthma, cancer cachexia, sepsis, nephritis, hepatitis, vasculitis, heart failure,
Hyperlipidemia, multiple sclerosis, neuropathy, myelopathy, dementia,
An object of the present invention is to provide a method for producing a medicament useful for the treatment or prevention of diseases such as diabetes and viral infection.

[0007]

Means for Solving the Problems As a result of various searches for metabolites of microorganisms, the present inventors have found that one strain belonging to actinomycetes has a cell growth inhibitory effect on mammalian cancer cells and a TNFα production inhibitory effect. Physiologically active substance, NK
30424AS-1, NK30424AS-2, NK3
The inventors have found that 0424BS-1 and NK30424BS-2 are produced, and completed the present invention. That is, the present invention provides the following formula (1)

Embedded image A microorganism having the ability to produce the compound represented by the formula is cultured in a nutrient medium, the compound represented by the formula (1) is produced and accumulated in the culture, and these are collected. A method for producing the compound represented by (1). The compound represented by the formula (1) is NK30424AS-
1, NK30424AS-2, NK30424BS-
1 or NK30424BS-2. The above-described production method, wherein the microorganism is a microorganism belonging to the genus Streptomyces. An actinomycete belonging to the genus Streptomyces having the ability to produce the compound represented by the above formula (1). About.

Hereinafter, the present invention will be described in detail.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION

In the production method of the present invention, a microorganism capable of producing the compound represented by the above formula (1) is cultured in a nutrient medium, and the compound represented by the formula (1) is added to the culture. It is characterized in that the compound is produced and accumulated, and these are collected. Examples of the compound represented by the above formula (1) include NK30424AS-1, NK30424AS-2,
NK30424BS-1 and NK30424BS-
2 is given. These are in a diastereomeric relationship with each other.

Hereinafter, NK30424AS-1, NK30
424AS-2, NK30424BS-1, NK304
2 shows the physicochemical properties of 24BS-2. a) NK30424AS-1 1) Appearance: White powder 2) Molecular formula: C ₃₀ H ₄₆ N ₂ O ₁₁ S (measured by high resolution mass spectrometry) 3) Molecular weight: 642 (M + H) ⁺ measured by FAB-MS = 643) 4) Hydrogen nuclear magnetic resonance spectrum: 400 MHz in heavy water
FIG. 1 shows the spectrum measured in step (1). 5) Solubility: soluble in water, methanol and dimethyl sulfoxide. Insoluble in normal hexane and ethyl acetate. 6) Color reaction: Positive below. Lydon-Smith, ninhydrin (orange), sulfuric acid, potassium permanganate 7) Rf value of thin-layer chromatography: 0.43 silica gel (silica gel 60F254 manufactured by Merck) using a thin layer, 1-butanol- Acetic acid-water (4:
1: 1) was used.

B) NK30424AS-2 1) Appearance: white powder 2) Molecular formula: C ₃₀ H ₄₆ N ₂ O ₁₁ S (measured by high-resolution mass spectrometry) 3) Molecular weight: 642 (measured by FAB-MS method ( M + H) ⁺ = 643) 4) Hydrogen nuclear magnetic resonance spectrum: 400 MHz in heavy water
FIG. 2 shows the spectrum measured in step (1). 5) Solubility: soluble in water, methanol and dimethyl sulfoxide. Insoluble in normal hexane and ethyl acetate. 6) Color reaction: Positive below. Lydon-Smith, ninhydrin (orange), sulfuric acid, potassium permanganate 7) Rf value of thin-layer chromatography: 0.43 silica gel (silica gel 60F254 manufactured by Merck) using a thin layer, 1-butanol- Acetic acid-water (4:
1: 1) was used.

C) NK30424BS-1 1) Appearance: white powder 2) Molecular formula: C ₃₀ H ₄₆ N ₂ O ₁₁ S (measured by high-resolution mass spectrometry) 3) Molecular weight: 642 (measured by FAB-MS method ( M + H) ⁺ = 643) 4) Hydrogen nuclear magnetic resonance spectrum: 400 MHz in heavy water
Fig. 3 shows the spectrum measured in the above. 5) Solubility: soluble in water, methanol and dimethyl sulfoxide. Insoluble in normal hexane and ethyl acetate. 6) Color reaction: Positive below. Lydon-Smith, ninhydrin (orange), sulfuric acid, potassium permanganate 7) Rf value of thin-layer chromatography: 0.43 silica gel (silica gel 60F254 manufactured by Merck) using a thin layer, 1-butanol- Acetic acid-water (4:
1: 1) was used.

D) NK30424BS-2 1) Appearance: white powder 2) Molecular formula: C ₃₀ H ₄₆ N ₂ O ₁₁ S (measured by high-resolution mass spectrometry) 3) Molecular weight: 642 (measured by FAB-MS method) M + H) ⁺ = 643) 4) Hydrogen nuclear magnetic resonance spectrum: 400 MHz in heavy water
Fig. 4 shows the spectrum measured in the above. 5) Solubility: soluble in water, methanol and dimethyl sulfoxide. Insoluble in normal hexane and ethyl acetate. 6) Color reaction: Positive below. Lydon-Smith, ninhydrin (orange), sulfuric acid, potassium permanganate 7) Rf value of thin-layer chromatography: 0.43 silica gel (silica gel 60F254 manufactured by Merck) using a thin layer, 1-butanol- Acetic acid-water (4:
1: 1) was used.

The physiologically active substance NK30424AS-1, N
K30424AS-2, NK30424BS-1, NK
30424BS-2 is obtained, for example, by culturing these producing bacteria belonging to the genus Streptomyces, producing the compound, and collecting from the culture.

Physiologically active substances NK30424AS-1, N
K30424AS-2, NK30424BS-1, NK
Representative examples of 30424BS-2 producing bacteria include, for example, Streptomyces sp. NA 30424 isolated from soil.
Strains. The bacteriological properties of this strain are shown below.

1. Morphological properties Observation after 2 weeks at 27 ° C. shows that the aerial hyphae are simply branched, the tip is helical, and no ring-shaped branches are formed. Neither sporangia nor zoospores are found. Spore surface is smooth, spores are cylindrical, size 0.5 ~
0.9 × 0.9 to 1.3 μm. In addition, spores are formed in a chain of 10 or more.

2. Growth in various media Table 1 below shows the growth state of each medium at 27 ° C for 2 weeks.

Table 1 Culture medium Growth mycelium Base mycelium Soluble pigment Glucose / asparagine Good Moderate, brown-ash to colorless-none Medium (ISP 5 med.) Bright gray tea light yellow (wettable) Starch / inorganic salt agar medium good Abundant, brownish white to light yellow- none (ISP 4 med.) Black (wettable) light yellow tea Tyrosine agar medium good Abundant, brown-white to light yellow-brown brown (ISP 7 med.) Light brown ash to light brown (wet) nutrient agar medium moderate, white to colorless to slightly light brown-ash light yellow-brown (wet) yeast Malt agar medium good moderate, brown ash to light yellow to slightly (ISP 2 med.) Light brown ash light yellow brown brownish (wettable) oatmeal agar medium good moderate, brown ash to colorless to none (ISP 3 med.) Light brown ash yellow

[0020] 3. Physiological properties Optimal growth temperature: 27-37 ° C Nitrate reduction: positive Starch hydrolysis (starch / inorganic salt agar): positive Peptoneization of skim milk: negative Negative liquefaction of gelatin: positive Generation of melanin-like pigment: positive 4. Utilization of carbon source (on Prideham-Godribe agar medium) L-arabinose + D-xylose + D-glucose + D-fructose + sucrose + inositol + L-rhamnose + raffinose-D-mannitol +

5. Diaminopimelic acid in cell wall LL-diaminopimelic acid. To summarize the above,
In this strain, the cell wall is LL-diaminopimelic acid, and the types of menaquinone are mainly MK-9 (H8) and MK-9.
-9 (H6). According to the method of the International Streptomyces genus project (abbreviated as ISP), the spore-forming mycelium forms in Section Spir.
The spore surface belongs to ales and the surface of the spores is smooth, and the color of the mature hyphae is gray color (Gray color-series) and exhibits black wettability (hygroscopic). It produces melanin-like pigments and presents brown soluble pigments in the medium. In addition, the color of the underlying mycelium changes from light yellow to light yellow brown. As a carbon source, L-arabinose, D-xylose, D-glucose, D-fructose, sucrose, inositol, L-rhamnose, D-mannitol are used, and raffinose is not used.

Based on the above properties, Bergey's Manual of Defectative Bacteriology, edited by R.E. Buffanan and NE Gibbons (Bergey's Manual of Deterministic Bacteriology)
(Eminitive Bacteriology), 8th edition, 1974
The 30424 strain was found to belong to the genus Streptomyces. Therefore, the present bacterium was used in Streptomyces sp.
No. 4. The strain has been deposited with the Institute of Biotechnology, Institute of Biotechnology, Japan as FERM P-16422.

Strains belonging to the genus Streptomyces used in the present invention, like other Streptomyces genus strains, tend to change their properties. For example, it can be easily mutated by artificial mutating means using ultraviolet rays, X-rays, chemicals and the like. Regardless of the thus obtained mutant strain, the physiologically active substance NK30424A which is the object of the present invention
S-1, NK30424AS-2, NK30424BS
All those capable of producing -1 or NK30424BS-2 can be used in the present invention.

According to the present invention, the physiologically active substance NK30424
AS-1, NK30424AS-2, NK30424B
To produce S-1 or NK30424BS-2, the strain is first aerobically cultured in a medium containing nutrients that can be used by actinomycetes. As the nutrient source, known ones conventionally used for cultivation of actinomycetes can be used,
For example, as a carbon source, glucose, glycerin, galactose, starch syrup, dextrin, sucrose, starch, molasses, animal and vegetable oils and the like can be used. Nitrogen sources include soy flour, wheat, wheat germ, corn steep,
Liquor, meat extract, peptone, yeast extract, ammonium sulfate, sodium nitrate, urea and the like can be used alone or in combination. In addition, if necessary, it is effective to add an inorganic salt capable of generating sodium, cobalt, chlorine, sulfuric acid, phosphoric acid, and other ions. It also helps the growth of fungi and the physiologically active substance NK3
0424AS-1, NK30424AS-2, NK30
Organic and inorganic substances that promote the production of 424BS-1 or NK30424BS-2 can be appropriately added.

As a culture method, a liquid culture method, particularly a submerged stirring culture method, is suitable. The temperature suitable for culture is 15-37.
C., but is often cultivated at around 26-30.degree. Bioactive substances NK30424AS-1, NK304
24AS-2, NK30424BS-1, or NK3
The production of 0424BS-2 varies depending on the culture medium and the culture conditions, but the maximum accumulation usually occurs between 1 and 10 days in both shaking culture and tank culture. When the accumulation amount of the compound in the culture reaches the maximum, the culture is stopped and the target substance is isolated from the culture solution.

The physiologically active substance NK30424AS-1, N
Upon collection from a culture solution of K30424AS-2, NK30424BS-1, or NK30424BS-2, purification can be carried out by appropriately combining ordinary separation means utilizing the properties thereof. That is, the culture solution is separated into a filtrate and cells by centrifugation or filtration, and the obtained filtrate is Diaion HP-20 (trade name, manufactured by Mitsubishi Kasei).
NK30424AS-1, NK30424 by eluting with a lower alcohol or acetone, or extracting with an organic solvent such as 1-butanol.
AS-2, NK30424BS-1, or NK304
A fraction of 24BS-2 can be obtained.

In addition to the above-mentioned methods, known methods used for collecting substances, such as adsorption / partition chromatography, gel filtration chromatography, scraping from thin-layer chromatography, high-performance liquid chromatography, etc., are appropriately combined, or NK3 by repeating
0424AS-1, NK30424AS-2, NK30
424BS-1 or NK30424BS-2 can be isolated pure.

NK30424AS-1, NK3 of the present invention
0424AS-2, NK30424BS-1, or N
As described below, K30424BS-2 is a physiologically active substance having a cell growth inhibitory activity on mammalian cancer cells and a TNFα production inhibitory activity.

[0029] NK30424AS will be described below with reference to test examples.
-1, NK30424AS-2, NK30424BS-
1 or NK30424BS-2 has a cell growth inhibitory effect on cancer cells and a TNFα production inhibitory effect.

Test Example 1 Cell Proliferation Inhibition Using a RPMI1640 medium supplemented with 5% fetal calf serum, mouse leukemia-derived cancer cells J774.1 were cultured at 37 ° C.
The cells were cultured under 5% CO ₂ . The cells were seeded on a 96-well plate, cultured for one day, and then NK30424AS-
1, NK30424AS-2, NK30424BS-
1 and NK30424BS-2, respectively. The drug treatment was performed for 3 days, and the degree of proliferation was evaluated by the MTT method. As a result, an IC ₅₀ value was determined from the dose-response curve, and the value is shown in Table 2.

Table 2 NK30424AS-1, NK30424AS-2, N
K30424BS-1 and NK30424BS-2
The cytostatic compound _{IC 50 (μM) NK30424AS-1} 0.07 NK30424AS-2 0.07 NK30424BS-1 0.06 NK30424BS-2 0.06

Test Example 2 Inhibition of TNFα Production Using mouse peritoneal macrophages induced by thioglycolate, NK30424AS-1, NK3042
4AS-2, NK30424BS-1, and NK30
The TNFα production inhibitory activity of 424BS-2 was measured. A test drug was added to a culture solution of the above cells (500,000 cells / well), and then lipopolysaccharide as a TNFα inducer was added to a final concentration of 100 ng / ml, followed by further culturing for 20 hours. TNFα in this culture solution
The concentration was quantified in a bioassay. The bioassay was carried out by a cytotoxicity test against L-929 (mouse connective tissue-derived cells) (Method of Kiener, PA et al., J. Im.
munol. 141, p. 870, (1988) with some modifications). As a result, an IC ₅₀ value was determined from a volume-response curve, and the value is shown in Table 3.

Table 3 NK30424AS-1, NK30424AS-2, N
K30424BS-1 and NK30424BS-2
Production inhibitory activity of compound IC ₅₀ (μM) NK30424AS-1 0.7 NK30424AS-2 0.7 NK30424BS-1 0.04 NK30424BS-2 0.03

As is clear from the test examples, the NK3 of the present invention
0424AS-1, NK30424AS-2, NK30
424BS-1 or NK30424BS-2 has a cytostatic effect on mammalian cancer cells and TNF
It has an α production inhibitory effect.

[0035]

EXAMPLES Examples of the present invention will be described below, but these are merely examples, and do not limit the present invention in any way, and various modifications are possible.

Example 1 NK30424AS-1, NK
30424AS-2, NK30424BS-1, NK3
Production of 024BS-2 (1) Fermentation As a medium for preparing a frozen bacterium and a seed, glycerin 2.
0%, glucose 1.0%, adipron E3 (manufactured by Ajinomoto) 0.5%, peptone (manufactured by Kyokuto) 0.5%, yeast extract 0.5%, dipotassium hydrogen phosphate 0.05%, magnesium sulfate 0 A medium consisting of 0.05% and 0.2% calcium carbonate was used.

The above medium was placed in a 500 ml Erlenmeyer flask.
The mixture was sterilized at 120 ° C. for 20 minutes, and the Streptomyces sp. NA 30424 strain (F
ERM P-16422) was inoculated with 1 to 2 platinum loops of the slant culture, and then infused with a rotary shaker at 27 ° C. and 200 rpm.
Cultured for days. To the obtained culture, the same volume of a 30% glycerin aqueous solution was added, and after stirring, 5 ml was dispensed at -80 ° C.
The frozen one was used as a frozen bacterium.

[0038] The thus obtained frozen bacterium was used in a similar medium 100
Two 500 ml Erlenmeyer flasks containing ml were inoculated immediately after thawing so that the inoculum amount was 1%, and cultured for 2 days under the same conditions, and this was used as a seed.

The production medium is composed of 8.0% starch syrup, 3.0% adipron E3 (manufactured by Ajinomoto), 0.05% dipotassium hydrogen phosphate, 0.05% magnesium sulfate and 0.2% calcium carbonate. The medium was used. The medium before sterilization was adjusted to pH 6.8 before use.

10 liters of the production medium was dispensed into 100 500 ml Erlenmeyer flasks, sterilized at 120 ° C. for 20 minutes, and transplanted with 1 ml of each of the above seeds, and placed on a rotary shaker at 27 ° C. and 200 rpm. For 4 days. After completion of the culture, 9 liters of the culture solution was adjusted to pH 5.5 with 6N hydrochloric acid, and then filtered to obtain 6.5 liters of a culture filtrate.

(2) Purification The filtrate was adsorbed on a 700 ml (φ46 × 420 mm) column of Diaion HP-20 (manufactured by Mitsubishi Kasei).
After washing with 700 ml of water and 2.1 liter of 35% methanol aqueous solution, elution was performed with 2.1 liter of 50% methanol aqueous solution and the same volume of 80% methanol aqueous solution, and the eluate was further concentrated to 385 ml. The concentrated solution was adjusted to pH 5.6 with dilute hydrochloric acid, and fat-soluble impurities were extracted and extracted twice with an equal amount of ethyl acetate. The obtained aqueous layer was concentrated to 90 ml, adjusted to pH 7.0 with an aqueous sodium hydroxide solution, and then equilibrated with 50 mM sodium phosphate buffer (pH 7.0) DEAE-Sephadex A-25 (Pharmacia). 300ml (φ40 ×)
The solution was passed through a column (240 mm) and further passed through the above buffer solution to obtain 204 ml of a non-adsorbed fraction. This was again adjusted to pH 5.5 with dilute hydrochloric acid, and methanol was added to make a 25% aqueous methanol solution. 250 ml (φ30 × 115 m
m) of Diaion HP-20SS (100-200 mesh, manufactured by Mitsubishi Kasei), and 200 ml of 25%
After washing with methanol aqueous solution, 40%, 50%, 60% methanol aqueous solution was eluted step by step with 500 ml each.
Fractionated. Among the fractions eluted with 50% and 60% methanol aqueous solution, those containing a large amount of the target substance were collected and freeze-dried to obtain 170 mg.

Next, this fraction was purified by reversed-phase high performance liquid chromatography. That is, PEG of the reversed phase column
An ASIL ODS (10φ × 250 mm, manufactured by Senshu Kagaku) was injected with a 50% aqueous methanol solution corresponding to 15.6 mg of the above fraction, and a 10 mM ammonium phosphate buffer (pH 7) mixed with 17% acetonitrile was used. It eluted at a development rate of 0.5 ml / min. NK30424
AS-1 was 27.8 minutes after injection, NK30424BS-1 was 29.7 minutes after injection, and NK30424AS-
2 and NK30424BS-2 eluted 31-34 minutes after injection. The same operation is repeated once more, and NK30
The eluted portions of 424AS-1 and NK30424BS-1 were collected, desalted using a column of Diaion HP-20SS, lyophilized, and 1.3 mg of NK30424.
AS-1 and 1.1 mg of NK30424BS-1 were obtained.

[0043]

Industrial Applicability According to the present invention, a physiologically active substance NK30424 having an inhibitory action on cancer cell growth and an inhibitory action on TNFα production is provided.
AS-1, NK30424AS-2, NK30424B
Methods for producing S-1 and NK30424BS-2 were provided. These are used as chemotherapeutics for malignant tumors, or for rheumatoid arthritis, Kawasaki disease, Crohn's disease, Behcet's disease, bronchial asthma, cancer cachexia, sepsis,
It can be used as a therapeutic or preventive drug for diseases such as nephritis, hepatitis, vasculitis, heart failure, hyperlipidemia, multiple sclerosis, neuropathy, myelopathy, dementia, diabetes, and viral infection.

[Brief description of the drawings]

FIG. 1: 4 measured in heavy water of NK30424AS-1
1 shows a 00 MHz hydrogen nuclear magnetic resonance spectrum.

FIG. 2: 4 measured in heavy water of NK30424AS-2
1 shows a 00 MHz hydrogen nuclear magnetic resonance spectrum.

FIG. 3. 4 measured in heavy water of NK30424BS-1
1 shows a 00 MHz hydrogen nuclear magnetic resonance spectrum.

FIG. 4. Measurement of NK30424BS-2 in heavy water
1 shows a 00 MHz hydrogen nuclear magnetic resonance spectrum.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/06 A61P 3/06 3/10 3/10 7/00 7/00 9/00 9/00 11 / 06 11/06 13/12 13/12 25/28 25/28 29/00 29/00 101 101 31/12 31/12 35/00 35/00 C07D 405/06 C07D 405/06 (C12P 17/16 (C12N 1: 465) (C12N 1/20 C12R 1: 465) (72) Inventor Takashi Harada 3-15-11 Haneda, Ota-ku, Tokyo F-term (reference) 4B064 AE54 CA04 CD01 CD09 CD13 CE10 CE11 DA05 4B065 AA50X AC12 AC14 AC15 BA22 BB03 BB14 BB19 BC01 BC02 BC03 BC09 BC26 BD14 CA18 CA34 CA44 4C063 AA01 BB05 CC80 DD10 EE01 4C086 AA02 AA04 BA10 BC22 GA02 GA07 GA16 GA17 MA01 MA04 NA14 ZA02 ZA36 ZA59 ZA62 ZA68 ZB35 ZBZ ZB33

Claims (4)

[Claims] (1) The following formula (1): A microorganism having the ability to produce the compound represented by the formula is cultured in a nutrient medium, the compound represented by the formula (1) is produced and accumulated in the culture, and these are collected. A method for producing the compound represented by (1). 2. The compound represented by the formula (1) is NK3042
4AS-1, NK30424AS-2, NK30424
The production method according to claim 1, wherein the production method is BS-1 or NK30424BS-2. 3. The method according to claim 1, wherein the microorganism is a microorganism belonging to the genus Streptomyces. 4. An actinomycete belonging to the genus Streptomyces having the ability to produce the compound represented by the formula (1) according to claim 1.